The application of continuous flow chemistry in the synthesis of iminosugars and c-glycosyl compounds
Bennett, Jack
Bennett, Jack
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Publication Date
2024-09-24
Type
doctoral thesis
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Abstract
Flow chemistry is a field of chemical synthesis which involves carrying out reactions in continuous streams of solvents. Despite the numerous potential advantages, flow chemistry has been applied in a limited number of areas in synthetic glycochemistry, such as oligosaccharide synthesis and deprotection steps. The main aim of this thesis is to apply continuous flow techniques in other areas of synthetic glycochemistry, and to provide a comparison with batch techniques for the reactions studied. Chapter 1 introduces carbohydrates and iminosugars, which are the main synthetic focus of this work. The bioactivity of iminosugars and major synthetic routes towards these substances are described. An overview of flow chemistry, its advantages over batch techniques and its application to date in glycochemistry is also included. Chapter 2 focuses on flow syntheses of iminosugars adapted from existing batch methods. This chapter includes a flow synthesis of 1-deoxynojirimycin (1-DNJ) and miglustat from an L-sorbose derivative, along with the synthesis of a C-glycosyl mannonojirimycin compound via cascade azide-alkene cycloaddition/aziridine formation/ring opening. Different protecting groups were also investigated for the synthesis of the mannonojirimycin structure. Chapter 3 describes the synthesis of new iminosugars in batch and flow, including protected deoxymannonojirimycin (DMJ) and L-DNJ structures via tandem intramolecular azide-alkene cycloaddition/aziridine formation/ring opening reactions. A Design of Experiments (DoE) study to improve the yield of the L-DNJ compound is discussed, and further attempts to improve yield via photosynthetic methods in batch and thermolysis in flow are also described. Additional synthetic modifications to the azide-alkene precursor with an aim to improve yield are also discussed. The main achievement was the development of a route to l-DNJ from D-xylose, which is also a new sequence. Chapter 4 details the application of cascade Wittig/intramolecular oxa-Michael additions to synthesise 2-(C-glycosyl)acetates under continuous flow conditions, from commercially available pyranoses. Access to higher temperatures in flow enabled the synthesis of these C-glycosyl compounds, while batch attempts are mostly unsuccessful using this method. A modified flow approach involving delayed addition of base (DBU), which further increased yields, is also described in this chapter. The flow synthesis of a precursor to b-D-galactopyranosyl-2-methylpropane, an inducer of protein synthesis in E. coli, is also described.
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University of Galway
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Attribution-NonCommercial-NoDerivatives 4.0 International